Angelman syndrome (AS) is a genetic neurological disorder that presents with seizure, ataxia, severe mental retardation, virtual absence of speech, and is genetically and biochemically associated with other cognitive disorders, such as autism and Rett syndrome. This project is designed with the ultimate goal of establishing the basis for future rational development of human AS interventions. The investigators present evidence which indicates that AS is potentially a treatable disorder. This exciting possibility is experimentally testable due in large part to the extraordinary utility of the Ube3am-/p+ mouse model. They have developed three distinct therapeutic interventions to determine if the Ube3am-/p+ mouse model phenotype can be rescued in a postnatal fashion through intervention (1) at the site of genetic abnormality, (2) at the downstream biochemical site of dysfunction, or (3) by directly modifying synaptic function. Because the availability of an effective treatment is often a criterion for inclusion of a condition on a newborn screening panel, their goal is to establish the preclinical viability of these therapeutic strategies, determine the temporal constraints for treatment, and identify the optimal molecular targets for future human therapeutic research. PROJECT NARRATIVE: Angelman syndrome (AS) is a genetic neurological disorder occurring in one in 12,000 population. Independent living is not possible for adults with AS. The goals of this project are to establish the viability of three distinct therapeutic strategies to ameliorate the severe cognitive impairments exhibited by AS individuals.